Medicaments containing pantothenic acid

ABSTRACT

This invention relates to medicaments and their use in the alleviation of inflammation and pain in joints.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.: 10/088,339, filed on Sep.10, 2002, which is the National Stage of International Application No.: PCT/GB00/03490, filed on Sep. 12, 2000, which claims the benefit of Great Britain Application No.: GB 9921985.9, filed on Sep. 16, 1999. Each of these three prior applications is incorporated herein by reference in its entirety.

TECHNICAL FIELD

This invention relates to medicaments and their use in the alleviation of inflammation and pain in joints.

BACKGROUND

Pain or loss of movement in joints is a common occurrence, particularly among the elderly or those who have suffered damage to cartilage, bone surfaces or ligaments. Standard methods of treatment include the administration of corticosteroids by injection into the site of the inflammation. However, relief tends to be temporary and long term use can carry a number of contraindications.

Pantothenic acid (sometimes known as vitamin B5) and its salts have been used as a dietary supplement and for treatment of bronchial asthma, hay-fever, sinusitis and neurodermatitis.

SUMMARY

It has now been found that pantothenic acid (or a pharmaceutically acceptable salt and/or a derivative or prodrug there of), when injected into an affected joint or in the region of an affected joint (e.g., a joint affected by, e.g., inflamed by, traumatic arthritis), can be used to treat (e.g., control, ameliorate, alleviate, reduce, eliminate, prevent, or delay the onset of) pain or inflammation associated with the affected joint.

Accordingly, in one aspect, this invention relates to the use of pantothenic acid or a derivative thereof (e.g., a pharmaceutically acceptable salt or prodrug there of) in the preparation of a medicament for administration by injection into the region of ajoint for alleviation of inflammation or pain.

In another aspect, this invention relates to a method of alleviating pain in an inflamed or painful joint of a mammal, which includes the administration of an effective amount of pantothenic acid or a derivative thereof by injection into the region of an inflamed or painful joint to obtain alleviation of said inflammation or pain.

In a further aspect, this invention relates to a method of alleviating inflammation and pain in an inflamed and painful joint of a mammal, which includes administration of an injectable composition consisting essentially of an effective amount of pantothenic acid or a derivative thereof, a solvent therefor, and an adjuvant selected from cysteine and glucosamine by injection into the region of an inflamed and painful joint to obtain alleviation of said inflammation and pain.

In one aspect, this invention relates to a method of alleviating inflammation and pain in an inflamed and painful joint of a mammal, which includes administration of an injectactable composition that includes about 500 mg of pantothenic acid or a derivative thereof and a solvent therfor by injection into the region of an inflamed and painful joint to obtain alleviation of said inflammation and pain.

In another aspect, this invention relates to a method of alleviating inflammation and pain in an inflamed and painful joint of a mammal, the method consisting of administration of an injectactable composition consisting of an effective pain relief amount of pantothenic acid or a derivative thereof and a solvent therfor by injection into the region of an inflamed and painful joint to obtain alleviation of said inflammation and pain.

In a further aspect, this invention relates to the use of pantothenic acid (or a pharmaceutically acceptable salt and/or a derivative or prodrug there of) in the preparation of a medicament (e.g., an injectable composition) for administration by injection into ajoint or into a body region that is closely adjacent to the joint for treatment (e.g., alleviation) of pain in a joint affected by (e.g., inflamed by) traumatic arthritis. The medicament or composition can include at least about 400 milligrams of pantothenic acid (or a pharmaceutically acceptable salt or prodrug there of).

In one aspect, this invention relates to a method of treating pain in ajoint inflamed by traumatic arthritis which includes injecting a solution that includes at least about 400 mg of pantothenic acid (or a pharmaceutically acceptable salt and/or a derivative or prodrug there of) into the inflamed joint, or injecting the solution into a site that is next to the inflamed joint but outside the capsule of the inflamed joint.

Embodiments can include one or more of the following features.

The joint can be affected by a disorder selected from tennis elbow, housemaid's knee, frozen shoulder, inflamed knee joints, and hip and/or back pain associated with inflammation or restricted movement in the spinal vertebrae (e.g., inflammation of spinal vertebrae).

The derivative can be a salt of pantothenic acid (e.g., a calcium salt).

The pantothenic acid or a derivative thereof can be administered as an aqueous solution.

The effective amount of pantothenic acid or a derivative thereof can be about 500 milligrams (mg).

The solution can be injected into a site that is next to the inflamed joint but outside the capsule of the inflamed joint. For example, the solution is injected into a site that is outside the capsule of the inflamed joint and within about 10 millimeters from the exterior surface of the capsule of the joint.

The pantothenic acid (or a pharmaceutically acceptable salt or prodrug thereof) can be the dextrorotatory isomer of pantothenic acid. In other embodiments, a pantothenic acid racemic mixture or an optically active dextrollevo pantothenic acid enantiomer mixture that includes >50% of the dextro enantiomer can be administered (also in the form of a salt or prodrug).

The pantothenic acid or a derivative thereof can be co-administered with a local anesthetic. In some embodiments, the local anesthetic can be co-administered as a separate injection. The pantothenic acid or the pharmaceutically acceptable salt thereof can be co-formulated with a local anaesthetic.

The pantothenic acid or a derivative thereof can be co-administered with cysteine or glucosamine.

The pantothenic acid or a derivative thereof can be co-administered with a surface active phospholipid (e.g., a joint lubricant such as dipalmitoyl-phosphatidyl choline or phosphatidyl glycerol). The surface active phospholipid can also include a mixture of dipalmitoyl-phosphatidyl choline and phosphatidyl glycerol. In some embodiments, the surface active phospholipid can be co-administered as a separate injection.

The injectactable composition of the pantothenic acid or a derivative thereof in the solvent can be injected into the joint. The aqueous solution can be injected directly into the site of the joint. The solution (e.g., aqueous solution) can be injected (directly) into the inflamed joint.

The inflamed joint can be a freely moving joint that is inflamed by traumatic arthritis.

In some embodiments, the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In some embodiments, the subject can be a mammal. In certain embodiments, the subject is a human.

The term “mammal” includes organisms, which include mice, rats, cows, sheep, pigs, rabbits, goats, and horses, monkeys, dogs, cats, and preferably humans. “An effective amount” refers to an amount of a compound that confers a therapeutic effect (e.g., treats, controls, ameliorates, prevents, delays the onset of, or reduces the risk of developing a disease, disorder, or condition or symptoms thereof) on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.001 mg/Kg to about 1000 mg/Kg, (e.g., from about 0.01 mg/Kg to about 1000 mg/Kg from about 0.1 mg/Kg to about I 000 mg/Kg).

The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

Pantothenic Acid

As used herein, the term “pantothenic acid” refers to a compound having the following chemical structure:

Pantothenic acid is a chiral molecule that contains one stereogenic center. As such, there are two possible optically active, enantiomeric forms of pantothenic acid, i.e., the dextrorotatory isomer (dextro) and the levorotatory isomer (levo). The preferred enantiomeric form of pantothenic acid is the dextro enantiomer. The term “pantothenic acid” includes both enantiomeric forms as well as mixtures thereof (e.g., the stereoisomeric mixtures described herein); and all tautomeric and rotamer forms.

Pantothenic acid is a naturally occurring substance in plant and animal tissue. A particularly rich source is royal jelly obtainable from honey bee colonies. It may be used in its naturally occurring state or as a chemically pure material. Synthetic methods of preparations include those described in U.S. Pat. Nos. 2,780,645; 2,845,456 and 2,934,428. As can be appreciated by the skilled artisan, further methods of synthesizing pantothenic acid, its salts and prodrugs will be evident to those of ordinary skill in the art.

See, e.g., R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989);

T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Pantothenic acid (or salts thereof) can also be obtained commercially.

In some embodiments, the methods can include administering optically active dextro-pantothenic acid (or salts or prodrugs thereof) that is substantially free of levo-pantothenic acid.

In some embodiments, the methods can include administering a racemic (i.e., an optically inactive) mixture of pantothenic acid (i.e. 50% of the dextro-enantiomer and 50% of the levo-enantiomer).

In some embodiments, the methods can include administering an optically active mixture of pantothenic acid that is other than a racemic mixture and which contains >50% of the dextro isomer. For example, the methods can include administering an enantiomer mixture having at least about 60% (e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%) of dextro-pantothenic acid.

In some embodiments, the pantothenic acid may be used in the form of a salt, e.g. a pharmaceutically acceptable salt) and/or a prodrug or derivative. Such a salt can be formed between a cation and the carboxylic acid group (in the form of a negatively charged carboxylate group). Suitable cations include alkali metal, e.g., sodium (Na⁺) or potassium (K⁺); alkaline earth metal, e.g., magnesium (Mg²⁺) or calcium (Ca²⁺); transition metals, e.g., zinc (Zn²⁺); or an ammonium cation such as tetramethylammonium ion. A preferred salt form of pantothenic acid is calcium pantothenate (i.e., the calcium salt of pantothenic acid). Examples of prodrugs include esters (e.g., derivatives in which one or both of the pantothenic acid hydroxyl groups is capped with an acyl group, such as an acetyl group or a substituted or unsubstituted benzoyl group; or derivatives having a carboxylic ester group, e.g., an alkyl or aryl ester group instead of a carboxylic acid group) and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds. Derivatives can include without limitation, e.g., pantetheine (the mercaptoethyl conjugated amide analogue of pantothenic acid ) and its dimer pantethine (i.e., the dimer of pantetheine).

Pharmaceutical Comioositions

In general, pantothenic acid (or a pharmaceutically acceptable salt or prodrug there of) can be administered in the form of composition, which can further include any conventional non-toxic pharmaceutically-acceptable diluents, carriers, adjuvants or vehicles. In certain embodiments, compositions can further include one or more additional therapeutic agents. In general, the compositions are in a form that is suitable for injection.

The term “pharmaceutically acceptable diluent, carrier, adjuvant, or vehicles” refers to a diluent, carrier, adjuvant or vehicle that may be administered to a subject (e.g., a patient), together with pantothenic acid (or a pharmaceutically acceptable salt or prodrug there of), and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the compositions of this invention include, but are not limited to, water, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-cc-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-γ-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

Methods of Treatment

Conditions

The methods described herein can be used for the treatment of several conditions associated with inflammation or reduced movement of joints (e.g., arthritic conditions, e.g., treatment of pain associated with these conditions).

In some embodiments, the methods can be used to treat pain in one or more joints of a subject that are affected by (e.g., inflamed by) traumatic arthritis or post-traumatic arthritis. As used herein, the term “traumatic arthritis” refers to arthritis that is caused from blunt, penetrating, or repeated trauma or from forced inappropriate motion of a joint or ligament. Symptoms of traumatic arthritis can include swelling, pain, tenderness, joint instability, and internal bleeding. In certain embodiments, the methods described herein can be used to treat a traumatic arthritic or a post-traumatic arthritic condition that typically occurs in only one joint at a time.

In certain embodiments, the methods described herein can be used to treat, or treat joints affected by (e.g., alleviate pain in ajoint affected by), e.g., tennis elbow, housemaid's knee, frozen shoulder, inflamed knee joints and hip pain and back pain (e.g., associated with inflammation or restricted movement in the spinal vertebrae).

In certain embodiments, the joint(s) can be affected by traumatic arthritis or post-traumatic arthritis, but not osteoarthritis (e.g., primary or secondary osteoarthritis) or rheumatoid arthritis. By way of example, the methods described herein can be used after the onset of traumatic arthritis in the affected joint, but prior to the onset of osteoarthritis (e.g., primary or secondary osteoarthritis) in the affected joint.

In certain embodiments, the methods can be used to treat a traumatic or post-traumatic condition resulting from an injury where the bone and cartilage of the knee do not heal properly.

In certain embodiments, the methods can be used to treat a traumatic or post-traumatic condition that develops after a serious fracture, torn ligament or a tear to the meniscus. For example, the methods can be used to treat a traumatic or post-traumatic condition that develops after a serious hip injury or fracture (e.g., an injury or fracture that can lead to avascular necrosis, in which the blood supply to the ball portion (the femoral head) of the thighbone is cut off and the bone begins to wither).

In certain embodiments, the methods can be used to provide temporary relief from pain associate with rheumatoid arthritis.

Affected Joints

As used herein, the term “joint” (or articulation) refers to the location at which two bones make contact or articulate. The methods described herein can be used to treat a variety of joints that are found in the human or animal body, such as “partly” or “slightly movable” joints or articulations (sometimes referred to as “amphiarthroses”) or “freely movable” joints or articulations (sometimes referred to as “diarthroses” or “sinovial”). For purposes of clarification, the above-mentioned descriptors are intended to describe the different, art-recognized physiological categories of joints that can be treated (if affected) using the methods of the invention. The above-mentioned descriptors as used in this context are not intended to describe the condition or performance level or ability of the affected joint.

In some embodiments, the affected joint can be a “partly” or “slightly movable” joint or articulation that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the terms “partly” or “slightly movable joint or articulation” and “amphiarthroses” refer to joints or articulations in which the contiguous bony surfaces are either connected by broad flattened disks of fibrocartilage, of a more or less complex structure, e.g., in the articulations between the bodies of the vertebrae; or are united by an interosseous ligament, e.g., as in the inferior tibiofibular articulation.

In some embodiments, the affected joint can be a “freely movable joint or articulation” that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the terms “freely movable joint or articulation” or “diarthroses” refer to joints or articulations in which the contiguous bony surfaces are covered with articular cartilage, and connected by ligaments lined by synovial membrane. The joint may be divided, completely or incompletely, by an articular disk or meniscus, the periphery of which is continuous with the fibrous capsule while its free surfaces are covered by synovial membrane. Such joints are typically capable of uniaxial, biaxial or polyaxial movement. In certain embodiments, the affect joint can include as part of its normal, physiological structure a space (synovial cavity) between the articulating bones (asinovial joint).

In certain embodiments, the affected joint can be a ball and socket joint (sometimes referred to as “enarthrosis” or “spheroidal joint”) that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the term “ball and socket joint” refers to ajoint formed by the reception of a globular head into a cup-like cavity, in which the distal bone is capable of motion around an indefinite number of axes, which have one common center. Nonlimiting examples of ball and socket joints include hip and shoulder joints.

In certain embodiments, the affected joint can be a condyloid joint (sometimes referred to as “condyloid articulation” or “ellipsoidal joint”) that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the term “condyloid joint” refers to a joint in which an ovoid articular surface, or condyle, is received into an elliptical cavity in such a manner as to permit of flexion, extension, adduction, abduction, and circumduction, but generally no axial rotation. A nonlimiting example of a condyloid joint is a wrist-joint.

In certain embodiments, the affected joint can be a saddle joint (sometimes referred to as “sellar joint” or “articulation by reciprocal reception“) that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the term “saddle joint” refers to a joint in which the opposing surfaces are reciprocally concavo-convex. The movements associated with a saddle joint are similar to those permitted for a condyloid joint. A nonlimiting example of a saddle joint is the carpometacarpal joint of the thumb.

In certain embodiments, the affected joint can be a hinge joint (sometimes referred to as “ginglymus”) that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the term “hinge joint” refers to a joint in which the articular surfaces are moulded to each other in such a manner as to permit motion generally in one plane, forward and backward, the extent of motion at the same time being considerable. The direction which the distal bone takes in this motion is typically not in the same plane as that of the axis of the proximal bone; there is usually a certain amount of deviation from the straight line during flexion. The articular surfaces of such joints can be connected together by relatively strong collateral ligaments, which form their chief bond of union. Nonlimiting examples of hinge joints include the interphalangeal joints and the joint between the humerus and ulna (elbow); the knee and ankle joints can also be included, even though they allow a slight degree of rotation or side-to-side movement in certain positions of the limb.

In certain embodiments, the affected joint can be a pivot joint (sometimes referred to as “trochoid joint” or “rotary joint”) that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the term “pivot joint” refers to a joint in which (where the movement is limited to rotation) the joint is formed by a pivot-like process turning within a ring, or a ring on a pivot, the ring being formed partly of bone, partly of ligament. For example, in the proximal radioulnar articulation, the ring is formed by the radial notch of the ulna and the annular ligament; here, the head of the radius rotates within the ring. As another example, in the articulation of the odontoid process of the axis with the atlas the ring is formed in front by the anterior arch, and behind by the transverse ligament of the atlas; here, the ring rotates around the odontoid process.

In certain embodiments, the affected joint can be a gliding joint (sometimes referred to as “arthrodial joint” or “plane articulation”) that is affected by one or more of the conditions described herein (e.g., traumatic arthritis). As used herein, the term “gliding joint” refers to a joint which admits of only gliding movement; it is typically formed by the apposition of plane surfaces, or one slightly concave, the other slightly convex, the amount of motion between them being limited by the ligaments or osseous processes surrounding the articulation. Nonlimiting examples of gliding joints include the joints between the articular processes of the vertebrae, the carpal joints, except that of the capitate with the navicular and lunate, and the tarsal joints with the exception of that between the talus and the navicular.

Modes of Administration

Dosages

In some embodiments, the methods can include administration of from about 400 milligrams to about 2000 milligrams (e.g., about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about I 100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, or about 2000) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

For ease of exposition, it is understood that any recitation of ranges or subranges of a particular range expressly includes each of the individual values that fall within the recited range, including the upper and lower limits of the recited range.

In some embodiments, the methods can include administration of from about 400 milligrams to about 2,000 milligrams (e.g., from about 400 milligrams to about 2,000 milligrams, from about 400 milligrams to about 1800 milligrams, from about 400 milligrams to about 1600 milligrams, from about 400 milligrams to about 1400 milligrams, from about 400 milligrams to about 1200 milligrams, from about 400 milligrams to about 1100 milligrams, from about 400 milligrams to about 1000 milligrams, from about 400 milligrams to about 900 milligrams, from about 400 milligrams to about 800 milligrams, from about 400 milligrams to about 700 milligrams, from about 400 milligrams to about 600 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of from about 500 milligrams to about 2,000 milligrams (e.g., from about 500 milligrams to about 2,000 milligrams, from about 500 milligrams to about 1800 milligrams, from about 500 milligrams to about 1600 milligrams, from about 500 milligrams to about 1400 milligrams, from about 500 milligrams to about 1200 milligrams, from about 500 milligrams to about 1100 milligrams, from about 500 milligrams to about 1000 milligrams, from about 500 milligrams to about 900 milligrams, from about 500 milligrams to about 800 milligrams, from about 500 milligrams to about 700 milligrams, from about 500 milligrams to about 600 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of from about 600 milligrams to about 2,000 milligrams (e.g., from about 600 milligrams to about 2,000 milligrams, from about 600 milligrams to about 1800 milligrams, from about 600 milligrams to about 1600 milligrams, from about 600 milligrams to about 1400 milligrams, from about 600 milligrams to about 1200 milligrams, from about 600 milligrams to about 1100 milligrams, from about 600 milligrams to about 1000 milligrams, from about 600 milligrams to about 900) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of from about 700 milligrams to about 2,000 milligrams (e.g., from about 700 milligrams to about 2,000 milligrams, from about 700 milligrams to about 1800 milligrams, from about 700 milligrams to about 1600 milligrams, from about 700 milligrams to about 1400 milligrams, from about 700 milligrams to about 1200 milligrams, from about 700 milligrams to about 1100 milligrams, from about 700 milligrams to about 1000 milligrams, from about 700 milligrams to about 900) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of from about 800 milligrams to about 2,000 milligrams (e.g., from about 800 milligrams to about 2,000 milligrams, from about 800 milligrams to about 1800 milligrams, from about 800 milligrams to about 1600 milligrams, from about 800 milligrams to about 1400 milligrams, from about 800 milligrams to about 1200 milligrams, from about 600 milligrams to about 1100 milligrams, from about 800 milligrams to about 1000 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of from about 900 milligrams to about 2000 milligrams (e.g., from about 900 milligrams to about 2,000 milligrams, from about 900 milligrams to about 1800 milligrams, from about 900 milligrams to about 1600 milligrams, from about 900 milligrams to about 1400 milligrams, from about 900 milligrams to about 1200 milligrams, from about 900 milligrams to about 1100 milligrams, from about 900 milligrams to about 1000 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of from about 1000 milligrams to about 2000 milligrams (e.g., from about 1000 milligrams to about 2000 milligrams, from about 1000 milligrams to about 1800 milligrams, from about 1000 milligrams to about 1600 milligrams, from about 1000 milligrams to about 1400 milligrams, from about 1000 milligrams to about 1200 milligrams, from about 1000 milligrams to about 1100 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In some embodiments, the methods can include administration of at least about 400 milligrams (e.g., at least about 500 milligrams, at least about 600 milligrams, at least about 700 milligrams, at least about 800 milligrams, at least about 900 milligrams, at least about 1000 milligrams). In certain embodiments, the methods can include administration of at least about 400 milligrams of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of (e.g., at least about 500 milligrams, at least about 800 milligrams, at least about 1000 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In certain embodiments, the methods can include administration of from about 400 milligrams to about 1200 milligrams of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In certain embodiments, the methods can include administration of from about 400 milligrams to about 600 milligrams (e.g., from about 450 milligrams to about 550 milligrams, e.g. about 500 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In certain embodiments, the methods can include administration of from about 700 milligrams to about 1200 milligrams of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In certain embodiments, the methods can include administration of from about 700 milligrams to about 900 milligrams (e.g., from about 750 milligrams to about 850 milligrams, e.g. about 800 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

In certain embodiments, the methods can include administration of from about 900 milligrams to about 1100 milligrams (e.g., from about 950 milligrams to about 1050 milligrams, e.g. about 1000 milligrams) of pantothenic acid, or a pharmaceutically acceptable salt or prodrug there of.

Injectable Compositions

In general, the compositions used in the methods described herein are in a form suitable for injection, e.g., in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous solution or a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in water or 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

In some embodiments, an injectable composition can prepared by dissolving the active ingredient, i.e., pantothenic acid or a salt thereof (e.g., a calcium salt) in a suitable solvent (e.g., water).

Site ofAdministration

In some embodiments, an injectable composition containing the active ingredient (e.g., pantothenic acid or a salt thereof, e.g., a calcium salt thereof) can be injected directly into the affected joint by intraarticular injection. For example, the injectable composition can be injected directly into the joint capsule (sometimes referred to as a “capsule of the joint” or “articular capsule”) of the affected joint by intra-articular injection. As used herein, the terms “joint capsule,” “capsule of the joint,” or “articular capsule” each refer to the two-layer structure that completely envelopes the freely movable bone joints. The outer layer of the joint capsule is typically referred to as the stratum fibrosum and is composed of white fibrous tissue. The inner layer of the joint capsule is typically referred to as stratum synoviale, which is a secreting layer.

In other embodiments, the injectable composition containing the active ingredient (e.g., pantothenic acid or a salt thereof, e.g., a calcium salt thereof) is not directly injected into the affected joint by intraarticular injection. Rather, the injection is made at a site that is outside of the affected joint, but still within the region of (e.g., in the vicinity of, next to, adjacent to, or closely adjacent to) the affected joint.

In some embodiments, the body region that serves as the site of the injection can be any body region surrounding the joint that is within about 20 millimeters (e.g. within about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 millimeters) in any direction from the affected joint or from the exterior surface of any associated housing structure enveloping the affected joint, such as a joint capsule.

In certain embodiments, the site of the injection can be any body region surrounding the joint that is within at most about 15 millimeters (e.g. within at most about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 millimeters, e.g., within at most about 10 millimeters or within at most about 5 millimeters) from the affected joint or from the exterior surface of any associated housing structure enveloping the affected joint, such as a joint capsule. For example, the site can be located outside of the joint capsule of the affected joint and within, e.g., about 5, 10, or 15 millimeters from the exterior surface of the stratum fibrosum of the joint capsule. While not wishing to be bound by theory, it is believed that the active ingredient can penetrate the joint by diffusion in this mode of administration.

In some embodiments, the site of injection can be determined on the basis of the size of the affected joint. For large joints, which can include the majority joints except for vertebrae, the injectable pharmaceutical composition may be injected into the capsule of the joint by intra-articular injection. For small joints, typically the vertebrae, injection outside of the joint or joint capsule is preferred, typically to avoid the risk of damage to the joint. This mode of administration also enables the use of large doses (and hence large volume injections), which would be otherwise difficult to accommodate in small joints. Typically the injection site for either mode of administration can be selected by the practitioner applying finger pressure to the joint, and asking the patient to identify the location of maximum pain.

Regimen

Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon, e.g., the host treated. A typical preparation will contain from about 5% to about 95% active ingredient (w/w). Alternatively, such preparations contain from about 20% to about 80% active ingredient.

In some embodiments, a typical dose is an aqueous solution (about 2 milliliters) containing about 500 mg of acid salt, which can be injected directly into the site of the inflamed joint or outside of the joint as described herein. A program of injections is generally desirable in which dosages similar to that indicated above are given at intervals of a few days (e.g., 2, 3, 4, 5, or 6 days) to about one week. Reduced inflammation and increased freedom of movement is usually noticeable after about a week from the initial injection. In certain embodiments, for larger doses (e.g., ≧1000 milligrams), the active ingredient can be provided in two or more closely spaced (e.g., from about 5 minutes to about 1 hour) and smaller doses (e.g., each independently about 400, about 500, or about 600 milligrams).

In some embodiments, the active ingredient (e.g., pantothenic acid or a salt thereof, e.g., a calcium salt thereof) can be coadministered with one or more other therapeutic agents (e.g., local anesthetic, cysteine, glucosamine, a surface active phospolipid).

In certain embodiments, the additional agents may be administered separately, as part of a multiple dose regimen, from the pantothenic acid, pantothenic acid salts, or pantothenic acid prodrugs (e.g., sequentially, e.g., on different overlapping schedules with the administration of the pantothenic acid active ingredients described herein). Alternatively, these agents may be part of a single dosage form, mixed together with the pantothenic acid active ingredients described herein in a single composition. In still another embodiment, these agents can be given as a separate dose (a separate injection) that is administered at about the same time that the pantothenic acid active ingredients described herein are administered (e.g., simultaneously with the administration of the pantothenic acid active ingredients described herein).

When the compositions of this invention comprise a combination of the pantothenic acid active ingredients described herein and one or more additional therapeutic or prophylactic agents, both the pantothenic acid active ingredients described herein and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

In certain embodiments, the initial treatment may cause some pain and it may, therefore, be desirable to co-administer a local anaesthetic, e.g. bupivicaine or lignocaine, at the same time or shortly before the injection of the pantothenic acid or salt or prodrug thereof (e.g., as a separate injection), or as a co-formulation with the pantothenic acid or salt or prodrug thereof.

In certain embodiments, other physiologically active materials may be co-administered, e.g. cysteine or glucosamine.

In certain embodiments, when injecting into a joint, it may also be helpful to co-administer within the same treatment regime, a surface active phospholipid (SAPL) such as dipalmitoyl-phosphatidyl choline (DPPC) or phosphatidyl glycerol (PG). Preferably, a mixture of DPPC and PG is employed. A preferred protein-free SAPL composition comprising a blend of DPPC and PG is available from Britannia Pharmaceuticals Ltd of Brighton Road, Redhill under the trade name ‘pumactant’. While not wishing to be bound by theory, SAPL's such as ‘pumactant’ are believed to act as a lubricant in joints, taking over to some extent the function of synovial fluid.

All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.

OTHER EMBODIMENTS

All of the features disclosed in this specification may be combined in any combination. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 

1. A method of treating pain in a joint inflamed by traumatic arthritis which comprises injecting a solution comprising at least about 400 mg of pantothenic acid or a pharmaceutically acceptable salt or a derivative or prodrug thereof into the inflamed joint, or injecting the solution into a site that is next to the inflamed joint but outside the capsule of the inflamed joint.
 2. The method of claim 1, wherein the solution is injected directly into the inflamed joint.
 3. The method of claim 1, wherein the solution is injected into a site that is next to the inflamed joint but outside the capsule of the inflamed joint.
 4. The method of claim 3, wherein the solution is injected into a site that is within about 10 millimeters from the exterior surface of the capsule of the inflamed joint.
 5. The method of claim 1, wherein the pantothenic acid is in the form of a salt.
 6. The method of claim 5, wherein the salt is the calcium salt.
 7. The method of claim 1, wherein the solution is an aqueous solution.
 8. The method of claim 1, wherein the pantothenic acid or the pharmaceutically acceptable salt thereof is co-formulated with a local anaesthetic.
 9. The method of claim 1, wherein a local anaesthetic is co-administered with the pantothenic acid or the pharmaceutically acceptable salt thereof in a separate injection.
 10. The method of claim 1, wherein the solution comprises about 500 mg of calcium pantothenate.
 11. The method of claim 1, wherein the inflamed joint is a freely moving joint that is inflamed by traumatic arthritis.
 12. The method of claim 1, wherein the pantothenic acid is dextro-pantothenic acid. 